Breast Cancer Disorganization (Rycroft Group)

In general, I am interested in investigating the communication schemes that allows a large number of cells with limited computational ability can perform complex signal processing and react appropriately. For my senior thesis, I am working with Prof. Chris Rycroft of the Applied Mathematics Dept. at Harvard to investigate the mechanical cues that breast cancer exerts on the surrounding breast tissue to coordinate tumor growth and disorganization. The nominal anatomy of breast tissue is characterized by a collection of hollow shells of cells known as acini that are connected by a series of ducts. In the healthy case, these acini are suspended in an extracellular matrix consisting of a uniform gel of collagen fibers. We are interested in one aspect of breast cancer development, where acini burst through the outer basement layer of the acinus and then spread across the rest of the tissue. Understanding the mechanisms by which this occurs is vital for developing treatment strategies to keep tumors localized enough to be effectively treated by surgery and/or radiation.

Interestingly, the architectual changes associated with breast cancer are often related to the stiffness of the tissue, suggesting that mechanics can be involved. A natural progression is then to reason about how cancerous cells can use the environment’s properties for some type of mechanical communication. Recent ex vivo studies done by the Liphardt Group at Stanford with acini in synthetic collagen gels have revealed an interesting phenomenon that could hold the key towards comprehending these physical properties. When cancerous acini are placed onto a collagen gel, long collagen cables are formed between the acini into a large network, along which malignant cells can travel, causing disorganization. Indeed, when these collagen fibers are cut and the acini are isolated, the cancerous cells, no longer able to become disorganized, coalesce into a more benign tumor that is easier to treat.

Our guiding hypothesis is that these phenomena can be explained by physics, where cells are capable of pulling on the local collagen strands to form the long fibers between the acini, which can be motivated by physical intuition. For my thesis, I am trying to create a minimal model that can demonstrate the three key behavior of these cancerous acini, hopefully providing a potential clue for the biological and physical cues at play:

Formation of collagen cables between adjacent acini

Disorganization of cells along collagen cables

Halting of disorganization process by cutting of cables

On this front, my challenges include creating models for cell motility, cell-cell adhesion, and the forces the cells can exert on the collagen. This is computationally exciting because it involves integrating a continuum simulation for collagen with a discrete one for the cells, effectively integrating ideas from multi-agent simulations and solid mechanics. At the same time, I am seeking to expand this work into a more generalizable software package where biologists can intuitively and efficiently simulate cells that can interact not only with each other, but also with a dynamic environment.